Thursday, January 16, 2014

In alveolar rhabdomyosarcoma, 70-75% of tumors carry the
Pax3:Foxo1a oncogene. This oncogene seems to account for a large
difference in the response to chemotherapy and radiation relative to
rhabdomyosarcomas that do not carry this fusion gene.

In a report just
released in PLoS Genetics, Ken from our lab reports that
Pax3:Foxo1a levels fluctuate during tumor cell replication, and that a primary
function of Pax3:Foxo1a seems to be “checkpoint adaptation” – the process of
giving the cell permission to continue cell division despite damage from
therapy… with the hopes that this damage can be later repaired, simply
tolerated – or may offer an advantage to the tumor cell as a result of newly
gained mutations/properties. The paper is freely available online at: http://www.plosgenetics.org/doi/pgen.1004107.

This incredible group of commercial fishermen in British Columbia support children with cancer and childhood cancer research while having a fun time. Their website and 2013 herring sale video can be seen at www.fishermenhelpingkidswithcancer.com.

Saturday, January 11, 2014

On Saturday Jan 10th was the Alex's Lemonade Stand "Lemon Ball". What a fabulous event, and a terrific community of supporters. In attendance was not only Charles, but also our collaborator DR. David Langenau from MGH (fish rhabdomyosarcoma expert) and his wife, Brenna. Dave and Brenna are pictured here.

Monday, January 6, 2014

Parents of children who died from rare cancer believe greater investment
in quality research is critical

PORTLAND, Ore. – An international consortium of researchers focused on identifying
new molecularly targeted drugs to treat the most fatal form of childhood brain
tumor, diffuse intrinsic pontine glioma, or DIPG, has been awarded nearly
$300,000 by The Lyla Nsouli
Foundation for Children's Brain Cancer Research, based in London,
England. The foundation was established in memory of 3-year-old Lyla Nsouli,
who died in January 2012 after a devastating five-month battle with DIPG.

Lyla’s parents, Nadim and Simone Nsouli, are hopeful their
contribution will help bring researchers closer to a cure: “Facing her sudden,
brutal diagnosis without any real option for treatment or survival is not an
experience any child or their family should ever have to bear. Significantly
greater investment in quality research is vital to improving the prognosis for
children like Lyla. We are determined that research can provide treatments and
eventually a cure for this cruel childhood cancer.”

To date, no treatment
does more than incrementally increase survival of children with DIPG. One
day a child may have a headache or unsteadiness, but the next day a family's
life and plans are tragically changed. A group of international researchers called
the DIPG Preclinical Consortium hopes to change this.

“Our first phase of drug
screening and tumor DNA sequencing couldn't have been possible without the
support of the Lyla Nsouli Foundation, the Cure Starts Now, Accelerate Brain Cancer
Cures and CureSearch Foundations. Now that we have drug leads, the hard work of
validating these begins. The Lyla Nsouli Foundation has been with us every step
of the way, both in terms of support and accountability — both matter,” said
consortium coordinator Charles Keller,
M.D., associate professor of pediatrics at Oregon Health &
Science University Doernbecher Children’s Hospital and the OHSU Knight Cancer Institute.

“The members of the
Children’s Oncology Group CNS committee express a deep sense of gratitude to the
Lyla Nsouli Foundation for funding the DIPG Preclinical Consortium,” said Amar Gajjar, M.D., chair of the brain
tumor committee for the National Cancer Institute-supported Children's Oncology Group (COG). “The grant from
the foundation has sparked a global effort to find new and effective therapies
using the latest technologies currently available against diffuse intrinsic pontine
glioma. The rapid translation of information from research laboratories to a
clinical protocol is an often sought aim for advancing cancer cure rates – the
grant from the Lyla Nsouli Foundation has made this dream a reality.”

Gajjar and Maryam Fouladi, M.D., co-chair of the COG brain tumor new agents committee and leader of itsPediatric Brain Tumor Consortium,
conceived the DIPG Preclinical Consortium with Keller: “Real-time science in
partnership with the community for a shared goal of finding a two-drug
combination to put into international clinical trials for DIPG.”

Consortium member Jacques Grill, M.D., Ph.D., Institut
Gustave-Roussy, Villejuif, France, innovates by creating living cell cultures
not from autopsy-derived tumor samples, but from biopsies from the
brainstem. This novel approach was initially controversial but is winning
acceptance, Keller noted.

“Grill and his colleague, Dr. Darren Hargrave at Great
Ormond Street Hospital, London, keep a clear line of communication so that the
consortium's results are reported in real time to the European clinical trial
groups to inform on that side of the Atlantic,” said Keller. “The scientific
teams are diverse due to the pressing nature of the need to understand and
treat DIPG.”

Each member will take a
different but complementary role to ensure the results of the robotic drug
screen of 17 autopsy- or biopsy-derived DIPG cultures can be validated in mouse
models.

"This collaboration
has been a wonderful opportunity to work together as a community to move the
field closer to an effective therapy for this terrible disease. I am hopeful
that, together and with the immense support from Lyla Nsouli Foundation, we
will make real strides forward now," said Michelle Monje, M.D., Ph.D., Stanford University Beirne Faculty
Scholar in Pediatric Neuro-Oncology, Stanford Cancer Institute, Lucile Packard
Children's Hospital.

"The DIPG
Preclinical Consortium offers hope where once there was very little. When my
son, Andrew, was diagnosed with DIPG in October 2007, I never imagined that
such a collaboration would exist a few short years later — a collaboration
where exceptional science and a remarkable patient community meet in partnership
to change the future for children like Andrew and Lyla," said DIPG parent Sandy Smith.

OHSU Doernbecher Children's Hospital ranks among the
nation’s "Best Children’s Hospitals."* It is one of only 22 National
Institutes of Health-designated Child Health Research Centers in the country
and ranks 39th for NIH awards to children's hospitals and their
university-affiliated department of pediatrics.**

Nationally recognized physicians and nurses at OHSU
Doernbecher provide a full range of pediatric care to tens of thousands of
children each year from Oregon, Southwest Washington and around the nation in a
family-centered environment. OHSU Doernbecher specialists also travel
throughout Oregon and Southwest Washington, caring for more than 3,000 children
at more than 200 outreach clinics in 15 locations. Neonatal and pediatric
critical care experts provide round-the-clock consultations to community
hospitals statewide through OHSU Doernbecher's state-of-the-art telemedicine
network.

*U.S. News & World Report 2013-14 Best Children’s
Hospitals

** National Association of Children’s Hospitals and Related
Institutions (NACHRI)

Saturday, January 4, 2014

We are grateful to the Alex's Lemonade Stand Foundation for funding to enable the translation of a basic science discovery to preclinical trials so that Children's Oncology Group phase I and II trials might be possible. The discovery of EphB4 as a therapeutic target in alveolar rhabdomyosarcoma was work of former HHMI medical student fellow, Imran Aslam (now a JHMI internal medicine resident). Working in collaboration with the Druker laboratory, Imran uncovered the EphB4-EphrinB2 as the potentially highest value target in rhabdomyosarcomas. This ALSF REACH award allows us to investigate an anti-EphB4 antibody in embryonal rhabdomyosarcoma, as well as an EphB4-nanoparticle sump in alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and osteosarcoma. This work will be carried on by our star muscle- and mouse models expert, Megan. Check back regularly for updates on Megan's progress!

project updates:

01/14/2014: Project Funded!02/06/2014: The immunocompromised mice
we will be using to test the efficacy of an anti-EphB4 antibody have arrived.
These mice will be used to create pilot orthotopic xenograft models of eRMS in
the coming weeks. [ picture: at center is Megan. ] 02/20/2014: This week, the first set of immunocompromised mice were
injected with Rh18 cells (a human derived eRMS cell line). This begins a pilot
study to demonstrate the latency with which a xenograft from this cell line will successfully
create tumors in the strain of mice that we will use for future Alex’s Lemonade
Stand experiments. In other strains of immunocompromised mice, Rh18 cells have
generated tumors in 6-8 weeks- we’ll have to wait and see if these mice follow
suit!02/27/2014: Currently we are growing a new cell line to inject into the
mice which are part of our pilot experiment. To be consistent between
experiments, we need the same amount of cells for each mouse we use. This new
cell line is a little slow growing; as it is with many other research
experiments, the hardest part is waiting!03/14/2014: more watchful waiting (nothing new).03/20/2014: A second round of cells have been injected into
immunocompromised mice this week to continue our pilot experiments for this Alex’s
Lemonade Stand project. Our next steps will be to observe these mice over the next few
weeks and take note of when the tumor cells engraft and begin to grow.03/27/2014: no new news. still in watchful waiting mode. 04/04/2014: still awaiting tumor development before initiating drug trials. 04/10/2014: Our pilot study is progressing nicely this week, with 3 of
our orthotopic xenograft mice developing tumors. We will continue to observe
our other injected mice for tumor development over the next several weeks.04/14/2014: See the blog posthttp://kellerlabblog.blogspot.com/2014/04/imrans-paper-published-in-pnas.html for a link to today's published PNAS paper on this topic. The studies in Imran's paper were the basis of this "next steps" project. 04/17/2014: The growth of the current tumors is progressing as expected.
Our second group of mice have not grown any tumors yet, but they are still
within the expected latency time for development. We continue to monitor them
daily.04/24/2014: New batch of EphinB2-neutralizing biological agent received from pharma partner, facilitating the next series of therapeutic studies. 05/08/2014: mouse studies about to start for EphinB2-neutralizing biological agent. 05/15/2014: This week our official investigation on the efficacy of an
EphrinB2-neutralizing agent has begun. The study mice arrived on Wednesday and
were injected with Rh18 cells, a well characterized human eRMS cell line. Using
our pilot data, we expect tumors to form within the next 2-3 months.
Additionally, our second pilot study is still ongoing; we are continually
monitoring the mice for development of tumors.05/21/2014: Rh18 xenograft studies still ongoing. 05/28/2014: not unexpectedly, still waiting on tumors to develop before treatments can begin...06/05/14: No new news to report this week.
We do not expect treatment on our experimental mice to begin for a few more
weeks, and we are continually monitoring both our initial pilot mice and
current experimental for tumor development.06/12/2014: Still patiently waiting this week for mice in both
experimental groups to develop tumors.
06/26/2014: Tissue microarrays of EphB4 and EphrinB2 on embryonal rhabdomyosarcoma are complete (it will take 1-2 weeks to analyze these with our pathologist collaborator). We are also still patiently monitoring our
immunocompromised mice for development of tumors. We are checking them 3 times
a week so as soon as tumors develop we can begin treatment. Stay tuned!

07/10/2014: Exciting news from the Keller Lab for our Alex’s Lemonade
Stand project this week! The immunocompromised mice have started growing small
tumors for the Rh18 eRMS cell line. In the coming
weeks, most will begin receiving either an EphrinB2-neutralizing agent or a
control drug. Each mouse will be monitored daily and tumors measured three times per week. This experiment is progressing on schedule
and the next few months should be full of interesting data.

07/18/2014: The Alex’s Lemonade Stand experiment is progressing nicely
this week. All mice are tolerating the dosage of the drug well, and are not
exhibiting any side effects/toxicity. Expression of EphB4 and EphrinB2 in a small set of human osteosarcoma samples verified (request for TMA sent to COG); early studies of neuroblastoma are promising. 07/31/2014: This week, our experimental mice
continue to be monitored daily. We will be wrapping up the in vivo testing in
the coming weeks, then moving on to the data analysis phase.08/08/2014: EphB4 and EphrinB2 immunohistochemistry optimized for canine osteosarcoma (for pets with spontaneous osteosarcoma a potential preclinical model to help the dogs, and plan for a human osteosarcoma trial.) Request sent to NCI comparative oncology program for canine TMA slides. Meanwhile, the Rh18 eRMS mouse studies with the EphrinB2-neutralizing agent are wrapping up.

08/21/2014: The in vivo portion of our Alex's Lemonade Stand project is
slowly coming to a close. This week some of the raw data analysis and number
crunching was started, although it will be several weeks until that is
finished. Additionally, there are various supporting experiments that still
need to be executed to fully determine the efficacy of the EphrinB2 blocking
agent. 09/11/2014: This week our supplemental experiments continue. We are now
using RT-PCR to examine the amount of metastasis in the harvested lungs of our
treated and control mice. These experiments are time consuming, but will help
us decide if the EphrinB2 neutralizing agent administered to the mice was effective in
diminishing the metastatic capability of RH18 cells.

10/02/2014: Canine osteosarcoma TMA's for staining received; COG neuroblastoma TMA slides approved but MTA still to perform; COG osteosarcoma TMA proposal still in review (since July). rt-pcr strategy for above EphrinB2 blocking agent mouse studies (completed) is in revision. Some delays occurred as Megan spent the last 3 weeks in a collaborator's lab at Cold Spring Harbor Laboratory for a new strategic collaboration. 10/16/2014: A few setbacks this week owing to the particularly specific
requirements of some molecular biology techniques. We have ordered a few new
reagents in an attempt to complete the RT-PCR experiments, and should be back
at the bench soon.10/30/2014: Our new reagents for the
revised experiments have just arrived, and soon we should have a clear picture
about the efficacy of the EphrinB2 blocking agent on lung metastasis.12/04/2014: Preclinical trial of sEphB4-HSA in Rh18 orthotopic xenografts is now complete. The next step is preclinical testing in a patient-derived xenograft (see the description of this autopsy-derived model).

12/31/2014: Project on short term
hold pending transfer of grant from OHSU to our new, bold adventure at
cc-TDI.01/06/2014: New lab atcc-TDI started!01/07/2014: Collaborators Ayeza Bajwa and Atiya Mansoor have completed analysis of human eRMS tissue microarrays with unexpected results that point to key differences in aRMS and eRMS with respect to EphB4 and EphrinB2 biology. 01/08/2015: ALSF REACH grant year 2 funding received... this is the first grant funding for cc-TDI ... thank you, ALSF!01/15/2015: Strategic meeting (teleconference) held including pharma and CSU partners to consider a companion animal trial for osteosarcoma using EphB4/EphrinB2 therapeutics. 01/27/2015: Integration of animal study underway by Matthew, including ongoing tissue analysis from these studies. 02/06/2015: We have begun considering approaches to separating cell-autonomous and tumor microenvironment contributions of EphB4-EphrinB2 signaling in eRMS. 02/13/2015: analysis of tumor cell vs stroma cell expression of EphB4 and EphrinB2 reveals distinct differences in alveolar and embryonal rhabdomyosarcomas.

our team

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a community resource for families

You Can Participate in our Novel Therapeutics Studies !

One would like to think that tangibly better treatments for rhabdomyosarcoma, medulloblastoma and other childhood cancers can be found in a matter of years, instead of tens of years. Finding new treatments starts with research, perhaps even a new research approach to identifying effective new treatments. The Children's Cancer Therapy Development Institutefocuses on finding molecules in childhood cancers that can be directly turned off or on by drugs so that the tumor stops growing. Behind our novel approach is the use of genetically-engineered mice. Our Pediatric Preclinical Testing Initiative uses mice modified from before birth so that at a certain age, and in a certain tissue, the same mutations found in a child’s cancer are activated in the mouse. These special mouse models of childhood cancer can be used to test a treatment to see whether the tumor growth and spread (metastasis) can be reversed. The specific aspect of these mice having normal immune systems is a real plus, too, because white blood cells play an important role in how tumors evolve and respond to therapy.

Our program is designed around community participation. Through the Children's Cancer Therapy Development Institute, you can contribute directly to this grass-roots initiative. Donations through small gifts or grants will assist in studying compounds that may be effective in treating such childhood cancers as alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, or medulloblastoma (the alveolar rhabdomyosarcoma model was featured by Dr. Keller's long time collaborator and former mentor, 2007 Nobel laureate Mario Capecchi, in his Nobel Prize lecture {see 16 minutes onward}.)

For additional information regarding supporting this program please contact Charles Keller at charles@cc-tdi.org. Results obtained through these studies will be shared with the National Cancer Institute’s Cancer Therapy Evaluation Program, as well as the Children’s Oncology Group, which designs clinical trials for childhood cancer.